Inhibition of HIV protease activity by heterodimer formation

Biochemistry. 1991 Jan 8;30(1):106-11. doi: 10.1021/bi00215a016.


The dimeric nature of the HIV protease has been exploited to devise a novel mode of inhibiting the enzyme. The use of defective monomers or nonidentical subunits to exchange with wild-type homodimers produces catalytically defective heterodimers. Incubation of the HIV1 or HIV2 protease with a 4-fold molar excess of an inactive mutant of HIV1 leads to 80 and 95% inhibition of enzyme activity, respectively. Incubating HIV1 and HIV2 proteases at a 1:5 ratio results in a 50% reduction of activity of the mixed enzymes. The HIV1/HIV2 heterodimer was identified by ion-exchange HPLC. The heterodimer may display a disordered dimer interface, thereby affecting the catalytic potential of the enzyme. This mechanism of inactivation is an example of a dominant negative mutation that can obliterate the activity of a naturally occurring multisubunit enzyme. Furthermore, it provides an alternative to active-site-directed inhibitors for the development of antiviral agents that target the dimeric interface of the HIV protease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cloning, Molecular
  • Escherichia coli / genetics
  • HIV Protease / genetics
  • HIV Protease Inhibitors*
  • HIV-1 / enzymology
  • HIV-2 / enzymology
  • Humans
  • Kinetics
  • Macromolecular Substances
  • Molecular Sequence Data
  • Plasmids
  • Protein Conformation
  • Recombinant Fusion Proteins / antagonists & inhibitors
  • Saccharomyces cerevisiae / genetics
  • Superoxide Dismutase / genetics


  • HIV Protease Inhibitors
  • Macromolecular Substances
  • Recombinant Fusion Proteins
  • Superoxide Dismutase
  • HIV Protease